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Mus musculus, Homo sapiens
10 Downloadable Samples
Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
Kinesin spindle protein (KSP) inhibition is known to be an effective therapeutic approach in several malignancies. Filanesib (Arry-520), a KSP inhibitor, has demonstrated activity in heavily pretreated multiple myeloma (MM) patients. The aim of this work was to investigate the activity of filanesib in combination with an IMiDs plus dexamethasone backbone, and the mechanisms underlying the potential synergistic effect. Results: Filanesib showed in vitro and in vivo synergy with all IMiDs plus dexamethasone treatment, particularly with the pomalidomide combination (PDF). Importantly, the in vivo synergy observed in this combination was more evident in large, highly proliferative tumors, and it was shown to be mediated by impairment of mitosis transcriptional control, an increase in monopolar spindles, cell cycle arrest and the induction of apoptosis in cells in proliferative phases. In addition, PDF increased the activation of the proapoptotic protein Bax, which has been previously associated with sensitivity to filanesib, and could potentially be used as a predictive biomarker of response to this combination. Conclusions: Our results provide preclinical evidence for the potential benefit of the combination of filanesib with pomalidomide and dexamethasone and es-tablished the basis for a recently activated trial being conducted by the Spanish MM group investigating this combination in relapsed MM patients.
Publication Title
The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 1 Downloadable Sample
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
Kinesin spindle protein (KSP) inhibition is known to be an effective therapeutic approach in several malignancies. Filanesib (Arry-520), a KSP inhibitor, has demonstrated activity in heavily pretreated multiple myeloma (MM) patients. The aim of this work was to investigate the activity of filanesib in combination with an IMiDs plus dexamethasone backbone, and the mechanisms underlying the potential synergistic effect. Results: Filanesib showed in vitro and in vivo synergy with all IMiDs plus dexamethasone treatment, particularly with the pomalidomide combination (PDF). Importantly, the in vivo synergy observed in this combination was more evident in large, highly proliferative tumors, and it was shown to be mediated by impairment of mitosis transcriptional control, an increase in monopolar spindles, cell cycle arrest and the induction of apoptosis in cells in proliferative phases. In addition, PDF increased the activation of the proapoptotic protein Bax, which has been previously associated with sensitivity to filanesib, and could potentially be used as a predictive biomarker of response to this combination. Conclusions: Our results provide preclinical evidence for the potential benefit of the combination of filanesib with pomalidomide and dexamethasone and es-tablished the basis for a recently activated trial being conducted by the Spanish MM group investigating this combination in relapsed MM patients.
Publication Title
The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 71 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Rhabdoid tumors (RTs) are aggressive tumors of early childhood that occur most often in brain (AT/RTs) or kidney (KRTs). Regardless of location, they are characterized by loss of functional SMARCB1 protein, a component of the SWI/SNF chromatin remodeling complex. The aim of this study was to determine genes and biological process dysregulated in common to both AT/RTs and KRTs. Gene expression for AT/RTs was compared to that of other brain tumors and normal brain using microarray data from our lab. Similar analysis was performed for KRTs and other kidney tumors and normal kidney using data from GEO. Dysregulated genes common to both analyses were analyzed for functional significance. Unsupervised hierarchical clustering of RTs identified 3 major subsets: 2 comprised of AT/RTs, and 1 of KRTs. Compared to other tumors, 1187, 663 and 539 genes were dysregulated in each subset, respectively. Only 14 dysregulated genes were common to all 3 subsets. Compared to normal tissue, 5209, 4275 and 2841 genes were dysregulated in each subset, with an overlap of 610 dysregulated genes. Among these genes, processes associated with cell proliferation, MYC activation, and epigenetic dysregulation were common to all 3 RT subsets. The low overlap of dysregulated genes in AT/RTs and KRTs suggests that factors in addition to SMARCB1 loss play a role in determining subsequent gene expression. Drugs which target cell cycle or epigenetic genes may be useful in all RTs. Additionally, targeted therapies tailored to specific RT subset molecular profiles should be considered.
Publication Title
Pediatric rhabdoid tumors of kidney and brain show many differences in gene expression but share dysregulation of cell cycle and epigenetic effector genes.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 18 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Molecular profiling of tumors has proven a valuable tool for identification of prognostic and diagnostic subgroups in medulloblastomas, glioblastomas and other cancers. However, the molecular landscape of atypical teratoid / rhabdoid tumors (AT/RTs) remains largely unexplored. To address this issue, we used microarrays to measure the gene expression profiles of 18 AT/RTs, and performed unsupervised hierarchical clustering to determine molecularly similar subgroups. Four major subgroups (clusters) were identified. These did not conform to gender, tumor location, or presence of monosomy 22. Clusters showed distinct gene signatures and differences in enriched biological processes, including elevated expression of choroid plexus genes in Cluster 4. In addition, survival differed significantly by cluster, with shortest survival (mean 4.7 months) in both Clusters 3 and 4 compared to Clusters 1 and 2 (mean 28.1 months). Analysis showed that multiple bone morphogenetic protein (BMP) pathway genes were up-regulated in the short survival clusters, with BMP4 showing the most significant up-regulation (270-fold). Thus, high expression of BMP pathway genes was negatively associated with survival in this dataset. Our study indicates that molecular subgroups exist within AT/RTs, and that molecular profiling of these comparatively rare tumors may be of diagnostic, prognostic and therapeutic value.
Publication Title
High expression of BMP pathway genes distinguishes a subset of atypical teratoid/rhabdoid tumors associated with shorter survival.
Sample Metadata Fields
Sex, Specimen part
View Samples- Danio rerio
- 3 Downloadable Samples
IlluminaHiSeq2000
Description
Human oncogenes involved in the development of hematological malignancies have been widely used to model experimental leukemia. Here, we used the fli1 promoter in zebrafish to target the expression of oncogenic HRAS to endothelial cells, including the hemogenic endothelium and observed the development of a myelo-erythroid proliferative disease. In larvae, the pathological phenotype is characterized by some disruption of the vascular system with prominent expansion of the caudal hematopoietic tissue, increase of expression of stem cell markers and myelo-erythroid specific genes and production of a large number of l-plastin leukocytes. In mosaic juveniles, increased number of hematopoietic blasts and arrest of myeloid maturation was found in kidney marrow. Peripheral blood showed delays of erythrocyte maturation and increased number of circulating myeloid progenitors. We found that the abnormal phenotype is associated with a down regulation of the Notch pathway as shown by the decrease of expression of Notch target genes, whereas overexpressing an activated form of Notch together with the oncogene prevents the expansion of the myelo-erythroid compartment. This study identifies the downregulation of the Notch pathway following an oncogenic event in the hemogenic endothelium as an important step in the pathogenesis of myelo-erythroid diseases and describes a number of potential effectors of this transformation. Overall design: Methods: mRNA profiles of transgenic zebrafish overexpressing the oncogene HRAS in endothelial cells (Tg(fli1ep:GAL4FF)ubs3; Tg(UAS:eGFP-HRASV12)io006); or expressing activate Notch in endothelial cells (Tg(fli1ep:GAL4FF)ubs3; tg(UAS:NICD)kca3) were generated by deep sequencing using Illumina HiSeq 2000. The sequence reads that passed quality filters were analyzed using the CLC bio Assembly Cell software (version 3.2) and the Ensembl (release 63) predicted cDNAs for the Zv9 genome assembly. qRT–PCR validation was performed using TaqMan and SYBR Green assays.
Publication Title
Targeting oncogene expression to endothelial cells induces proliferation of the myelo-erythroid lineage by repressing the Notch pathway.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 28 Downloadable Samples
- Illumina HiSeq 2500
Description
Pluripotent stem cells can switch their unique metabolic requirements to facilitate cellular changes but it is not clear if adult stem cells utilize metabolism in a similar manner. Here we studied the metabolism of a human adult stem cell: dental pulp stem cells (DPSCs). The dental pulp from third molars of a diverse patient group was surgically extracted, generating cells that had a high percentage of mesenchymal stem cell markers CD29, CD44, CD146 and Stro1 and had the ability to differentiate into osteogenic and adipogenic lineages. Through RNA seq analysis we identified homeobox protein, Barx1, as a marker for DPSCs. Furthermore, using high throughput proteomic analysis we identified markers for DPSC populations with accelerated replicative senescence. In particular, we show that the transforming growth factor-beta (TGF-ß) pathway and the proteins associated with muscle contraction are upregulated in rapid aging DPSCs, indicating a loss of stem cell characteristics and spontaneous initiation of terminal differentiation. Importantly, using metabolic flux analysis, we identified a metabolic signature for the rapid aging DPSCs. This metabolic signature can be used to predict the onset of replicative senescence phenotypes. Hence, the present study identifies Barx1 as a DPSCs marker and dissects the first predictive metabolic signature for DPSCs aging. Overall design: We did RNA-seq of dental pulp stem cells (DPSC) using our own approach (ID# 29, 43, 44, 45), as well as commercial DPSC and mesenchymal stem cells (MCS) from Lonza.
Publication Title
Metabolism as an early predictor of DPSCs aging.
Sample Metadata Fields
Specimen part, Subject
View Samples
GSE35516- Mus musculus
- 30 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Hepatocyte-specific mutation of both NF-κB RelA and STAT3 abrogates the acute phase response in mice.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
A common response to physiological duress is the hepatic acute phase response, a process during which the expression of many genes is altered in the liver. Amongst these transcripts are those encoding acute phase proteins, defined as circulating proteins with significantly changed concentrations during an acute phase response. The goal of this study was to determine the influence of two transcription factors, STAT3 and NF-kappaB p65 (RelA), on hepatic gene changes including but not limited to acute phase proteins during bacterial pneumonia.
Publication Title
Hepatocyte-specific mutation of both NF-κB RelA and STAT3 abrogates the acute phase response in mice.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Radiotherapy is widely used to treat human cancer. Patients locally recurring after radiotherapy, however, have increased risk of metastatic progression and poor prognosis. The clinical management of post-radiation recurrences remains an unresolved issue. Tumors growing in pre-irradiated tissues have an increased fraction of hypoxic cells and are more metastatic, a condition known as tumor bed effect. Here we demonstrate that tumor cells growing in a pre-irradiated bed, or selected in vitro though repeated cycles of severe hypoxia, retain an invasive and metastatic capacities when returned to normoxia. HIF activity, while it facilitates metastatic spreading of tumors growing in a pre-irradiated bed, is not essential. Through gene expression profiling and gain and loss of function experiments, we identified the matricellular protein CYR61 and aVb5 integrin, as proteins cooperating to mediate these effects. Inhibition of aVb5 integrin suppressed invasion and metastasis induced by CYR61 and attenuated metastasis of tumors growing within a pre-irradiated field. These results represent a conceptual advance to the understanding of the tumor bed effect and identify CYR61 and aVb5 integrin as proteins that co-operate to mediate metastasis. They also indicate aV integrin inhibition a potential therapeutic approach for preventing metastasis in patients at risk for post-radiation recurrences, which can be promptly tested in the clinic.
Publication Title
CYR61 and alphaVbeta5 integrin cooperate to promote invasion and metastasis of tumors growing in preirradiated stroma.
Sample Metadata Fields
No sample metadata fields
View Samples